The present invention is directed to neuroprotective (antiischemic excitatory amino acid receptor blocking) 2-(4-hydroxypiperidino)-1-alkanol derivatives defined by formula (I) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of stroke, traumatic injury to the brain and spinal cord, and neuronal degenerative diseases including (but not limited to) senile dementias such as Alzheimer's disease, Huntington's disease and Parkinson's disease in mammals, especially humans; and to certain intermediates therefor.
Ifenprodil (A) is a racemic, so-called dl-erythro compound having the relative stereochemical formula ##STR1##
which is marketed as a hypotensive agent, a utility shared by a number of close analogs. Carron et al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp. 1992-1999 (1971). More recently, ifenprodil has been shown to possess antiischemic and excitatory amino acid receptor blocking activity. Gotti et al., J. Pharm. Exp. Therap., v. 247, pp. 1211-21 (1988); Carter et al., loc. cit., pp. 1222-32 (1988).
See also French Patent 2546166 and EPO publication EP-A1-351282, published Jan. 17, 1990. A goal, substantially met by the present invention, has been to find compounds possessing neuroprotective activity in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain 1-phenyl-3-(4-aryl-4-acyloxy-piperidino)-1-propanols have also been reported to be useful as analgesics, U.S. Pat. No. 3,294,804; 1-[4-(amino- and hydroxy-alkyl)phenyl]-2-(4-hydroxy-4-tolylpiperazino)-1-alkanols and alkanones have been reported to possess analgesic, antihypertensive, psycho-tropic or antiinflamatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A); and 2-piperidino-1-alkanol derivatives have been reported to be active as antiischemics, EP 398,578-A and Der 90-350,327/47.